Infectious complications are common and critical to patients who are malnourished, sustaining surgical complications, or requiring prolonged intensive care unit (ICU) stays. Despite intravenous (IV) nutrition, multiple antibiotics, and aggressive ICU care, mortality from sepsis (i.e., the presence of pathogenic organisms or their toxins in the blood or tissues) averages 30% with a range of 20–60% depending upon the patient population studied (Bone, et al. (1989) Cri. Care Med. 17:389–393; Bone, et al. (1987) N. Eng. J. Med. 317:653–658; Ziegler, et al. (1991) N. Eng. J. Med. 324:429–436; Hinshaw, et al. (1987) N. Eng. J. Med. 317:659–665; and Kreger, et al. (1980) Am. J. Med. 68:344–55). Septic morbidity, especially pneumonia, is significantly reduced in these patients when enteral feeding, feeding through a tube into the stomach, is used versus intravenous feeding or no feeding at all is provided (Kudsk, et al. (1996) Ann. Surg. 224:531–543; Moore, et al. (1986) J. Trauma 26:874–881; Moore, et al. (1989) J. Trauma 29:916–923; Moore, et al. (1992) Ann. Surg. 216:172–183).
The mechanisms responsible for improved recovery with the use of enteral feeding are poorly understood, but it is hypothesized that lack of enteral feeding leads to a breakdown in the gastrointestinal barrier, allowing molecules and perhaps pathogens to enter the body resulting in inflammation and distant infection (Deitch (1990) J. Trauma 30:S184–S189; Deitch (1990) Surgery 107:411–416; Ziegler, et al. (1988) Arch Surg. 123:1313–1319; Deitch, et al. (1987) Ann. Surg. 205:681; Deitch (1988) Perspect. Crit. Care 1:1–31. Most investigators have studied barrier integrity by focusing on changes in gut morphology and permeability to bacteria and macromolecules (Bushman, et al. (1993) Gastroenterology 104:A612).
Immunoglobulin A (IgA) and secretory IgA (sIgA) are the primary immunological defenses against many mucosal infections to prevent loss of barrier integrity (Svanborg, et al. In: Handbook of Mucosal Immunology (Orga et al., eds.) pp. 71–78; Killian, et al. In: Handbook of Mucosal Immunology (Orga et al., eds.) pp. 127–140). Agents which stimulate sIgA levels in the body include neuropeptides such as bombesin and gastrin-releasing peptide. Intestinal sIgA binds or agglutinates bacteria, viruses, and potentially other toxic molecules which are key to invasive mucosal infection, i.e., IgA prevents adherence of infectious agents to human mucosal cells (Svanborg, et al. In: Handbook of Mucosal Immunology (Orga et al., eds.) pp. 71–78).
Bombesin, a tetradeca-neuropeptide analogous to mammalian gastrin-releasing peptide, is known to stimulate release of a variety of gastrointestinal hormones including gastrin, somatostatin, cholecystokinin, pancreatic polyneuropeptide, insulin, glucagon, and neurotensin (Pascual, et al. In: Handbook of Mucosal Immunology (Orga et al., eds.) pp. 203–216; Debas, et al. (1991) Am. Surg. 161:243–249). These hormones then stimulate gastric, pancreatic, and intestinal secretions. In addition, bombesin increases the levels of intestinal sIgA (Debas, et al. (1991) Am. Surg. 161:243–249), reduces bacterial translocation (Haskel, et al. (1993) Ann. Surg. 217:634–643), and improves mortality in a lethal enterocolitis model (Chu-Ku, et al. (1994) Ann. Surg. 220:570–577). Bombesin may also up-regulate specific cellular immunity, either directly or acting through other hormones released in response to its administration (Jin, et al. (1989) Dig. Dis. Sci. 34:1708–1712).
In experiments using IV administration of bombesin to stimulate human natural killer (NK) cell activity against human K-562 tumor cells, in vivo bombesin infusion produced a greater antitumor response than in vitro bombesin incubation, suggesting that mediators other than bombesin may be involved in the increased mobilization of active NK cells in the blood stream ((Van Tol, et al. (1993) J. Neuroimmunol. 42:139–145). In addition, peripheral blood lymphocytes contain receptors for neurotensin, a neuropeptide released in response to bombesin administration (Evers, et al. (1994) Surgery 116:134–140).
Bombesin has been mainly studied for its satiety effect in humans (Gibbs, et al. (1998) Ann. N.Y. Acad. Sci. 547:210–216); Hilderbrand, et al. (1991) Regulatory Neuropeptides 36:423–433; Muurahainen, et al. (1993) Am. J. Physiol. 264: 350–R354; Flynn (1994) Ann. N.Y. Acad. Sci. 739:120–134; Lee, et al. (1994) Neurosci. Biohav. Rev. 18:313–232). However, binding sites for gastrin-releasing neuropeptide have been documented in human bronchi from specimens obtained from patients undergoing thoracotomy for carcinoma (Baraniuk, et al. (1992) Neuropeptides 21:81–84), and bombesin, as well as other neuropeptides, has been found in the respiratory epithelium of the nasal passages (Hauser-Kronberger, et al. (1993) Acta Otolaryngol. 113:387–393; Gawin, et al. (1993) Am. J. Physiol. 264:L345–350). Moreover, exogenous administration of bombesin stimulates both in vivo and in vitro human nasal mucus and serous cell secretions, thus increasing total protein, lysozyme, and glycoconjugate secretion, and, thereby, acting as a secretagogue in the upper respiratory tract passages (Baraniuk, et al. (1992) Am. J. Physiol. 262:L48–L52). No increase in albumin secretion accompanies this increased secretion, suggesting that bombesin does not exert its effects through vasodilation, increases in vascular permeability, or increases in plasma transit across the epithelium.
Investigators who have generated derivatives of bombesin or bombesin-like peptides have focused on amino acid modifications for enhancing antagonist activity. Such modifications include replacement of L-amino acids with D-amino acids; replacement of peptide bonds with non-peptide bonds; replacement of a natural amino acid with a synthetic amino acids such as statine, an AHPPA, or an ACHPA, a β-amino acid, or a γ-amino acid residue; and deletion of the C-terminal amino acid residue (U.S. Pat. No. 6,307,017 to Coy et al.; U.S. Pat. No. 5,428,019 to Edwards et al.; U.S. Pat. No. 5,736,517 to Bogden et al.; U.S. Pat. No. 5,428,018 to Edwards et al.; and U.S. Pat. No. 5,552,520 to Kim et al.).
There remains a need in the art for compositions of bombesin that are small, easy to synthesize, and suitable for pharmaceutical manufacturing and administration.